When to Use Antibiotics in Acute Exacerbation of Chronic Obstructive

Pulmonary Disease

Stephanie Manning, Pharm.D. CandidateOUHSC College of Pharmacy

Seminar – PHAR 7970March 10, 2011

Summary of Topics

• COPD overview– Epidemiology, definition, and pathogenesis

• Current research

• Current guidelines

• Application of research data

• Future directions

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Objectives

1. Identify 3 symptoms which change acutely during a COPD exacerbation.

2. Outline the 5 components of the proposed model of pathogenesis of bacterial exacerbations.

3. Assess the need for antibiotic therapy in a patient experiencing a COPD exacerbation according to current guidelines.

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Overview of COPD

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Question

The fourth leading cause of death in the United States is:

a) Heart disease

b) Cancer

c) Chronic obstructive pulmonary disease (COPD)

d) Cerebrovascular accidents

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EpidemiologyPrevalence• 2001: 12.1 million over age 25 in the U.S.• > 40 years of age• Men > Women

Morbidity and Mortality• 8 million office/hospital outpatient visits and 1.5 million ER

visits in the U.S. in the year 2000• Men: 46.4 deaths per 100,000• Women: 34.2 deaths per 100,000

Centers for Disease Control and Prevention Chronic Obstructive Pulmonary Disease (COPD) page. CDC website: http://www.cdc.gov/copd/data.htmGlobal Strategy for the Diagnosis, Management and Prevention of COPD, 2010. Available from: http://www.goldcopd.org.Williams DM, et al. Chronic Obstructive Pulmonary Disease. In: DiPiro JT, et al, eds. Pharmacotherapy: a pathophysiologic approach. 7th ed, 2008.

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Stable COPD• Chronic disease

• Loss of lung function

• Airflow limitation and abnormal inflammatory response

• Diagnosis based on:– Symptoms– History of exposure: tobacco smoke, occupational dusts

and chemicals

Williams DM, Bourdet SV. Chronic Obstructive Pulmonary Disease. In: DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: a pathophysiologic approach. 7th ed. McGraw-Hill Companies, Inc; 2008: 495-499. 7

Exacerbation of COPD• Acute change in baseline symptoms:

– Dyspnea, cough, and/or sputum production

• Consequences:– Decreased quality of life– Accelerated lung function decline– Increased mortality– Increased resource utilization and costs

Williams DM, Bourdet SV. Chronic Obstructive Pulmonary Disease. In: DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: a pathophysiologic approach. 7th ed. McGraw-Hill Companies, Inc; 2008: 495-499.

Can Respir J 2008;15 (Suppl A):1A-8A. 8

Exacerbation: Goals of Therapy• Prevention of hospitalization or reduction in

hospital stay

• Prevention of acute respiratory failure and death

• Resolution of symptoms

• Return to baseline

Williams DM, Bourdet SV. Chronic Obstructive Pulmonary Disease. In: DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: a pathophysiologic approach. 7th ed. McGraw-Hill Companies, Inc; 2008: 495-499. 9

Pathogenesis and Infection

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Etiology of COPD Exacerbations

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Infectious Noninfectious

~20% Mucoid Sputum

~20% Mucoid Sputum

Viral

~40-50%~40-50%Atypical

~5-10%Bacterial-viral co-

infection may occur

~5-10%Bacterial-viral co-

infection may occur

Bacterial

~40-50%~40-50%

Allergies, smoking, pollution, stress;

undertreatment or nonadherence in established COPD

Allergies, smoking, pollution, stress;

undertreatment or nonadherence in established COPD

Anzueto A. Primary care management of chronic obstructive pulmonary disease to reduce exacerbations and their consequences. Am J Med Sci. 2010;340(4):309-318.

Purulent SputumPurulent Sputum

Bacteria as a Cause of Exacerbation• Common bacteria:

– Haemophilus influenzae– Streptococcus pneumoniae– Moraxella catarrhalis– Pseudomonas aeruginosa

• Indicators of bacterial infection– Bronchoscopic sampling in pooled analysis of studies– Purulent sputum

Sethi S, Murphy TF. Infection in the pathogenesis and course of chronic obstructive pulmonary disease. N Engl J Med. 2008;359:22. 12

Proposed Model of Pathogenesis

Acquire new bacterial strain

Change in airway/systemic inflammation

Change in airway/systemic inflammation

Pathogen virulenceHost lung defense

Pathogen virulenceHost lung defense

Increased respiratory symptoms

Increased respiratory symptoms

Strain-specific immune response,

+/- Antibiotics

Strain-specific immune response,

+/- Antibiotics

Elimination of infecting strainElimination of infecting strain

Sethi S, Murphy TF. Infection in the pathogenesis and course of chronic obstructive pulmonary disease. N Engl J Med. 2008;359:22. 13

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Adapted from Sethi S, Murphy TF. Infection in the pathogenesis and course of chronic obstructive pulmonary disease. N Engl J Med . 2008;359:22.

Innate Lung Defense

• Disruption of innate lung defense

• Impaired mucociliary clearance

• Impaired phagocytosis of alveolar macrophage

• Epithelial cells as physical barrier and orchestrators of host defense

Proposed Model of Pathogenesis

Acquire new bacterial strain

Acquire new bacterial strain

Change in airway/systemic inflammation

Change in airway/systemic inflammation

Pathogen virulenceHost lung defense

Pathogen virulenceHost lung defense

Increased respiratory symptoms

Increased respiratory symptoms

Strain-specific immune response,

+/- Antibiotics

Strain-specific immune response,

+/- Antibiotics

Elimination of infecting strainElimination of infecting strain

Sethi S, Murphy TF. Infection in the pathogenesis and course of chronic obstructive pulmonary disease. N Engl J Med. 2008;359:22. 15

COPD Exacerbation Treatment: Role of Antibiotics

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Exacerbation Treatment

• Oxygen therapy

• Dose/frequency of bronchodilators

• Glucocorticosteroids

• Mechanical ventilation

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• Antibiotics

Global Strategy for the Diagnosis, Management and Prevention of COPD, 2010. Available from: http://www.goldcopd.org.

Controversy Over Antibiotic Use

• Overuse can lead to resistance

• 20% of exacerbations are noninfectious

• Mixed results from studies

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Current Research

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Ofloxacin vs. Placebo

• Study design: Prospective randomized controlled trial

• Objective

• Therapy: ofloxacin vs. placebo

• Primary outcome measures

20Nouira S, et al. Once daily oral ofloxacin in chronic obstructive pulmonary disease exacerbation requiring mechanical ventilation; a randomised placebo-controlled trial. Lancet. 2001;358:2020-25.

Results

21Nouira S, et al. Once daily oral ofloxacin in chronic obstructive pulmonary disease exacerbation requiring mechanical ventilation; a randomised placebo-controlled trial. Lancet. 2001;358:2020-25.

Doxycycline vs. Placebo

• Study design: Prospective randomized controlled trial

• Objective

• Therapy: doxycycline vs. placebo

• Primary and secondary outcome measures

22Daniels, et al. Antibiotics in addition to systemic corticosteroids for acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2010;181:150-157.

Results

23Daniels, et al. Antibiotics in addition to systemic corticosteroids for acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2010;181:150-157.

Early Antibiotic Administration

• Study design: Retrospective cohort

• Objective

• Primary and secondary outcome measures

24Rothberg MB, et al. Antibiotic therapy and treatment failure in patients hospitalized for acute exacerbations of chronic obstructive pulmonary disease. JAMA. May 2010;303(20):2035-2042.

Cohort Study Design

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Treatment Failure

No Treatment Failure

Treatment Failure

No Treatment Failure

Study design. Duke University Medical Center Library. http://www.mclibrary.duke.edu/subject/ebm/studies.html. last modified 8-26-2008. (Accessed 2-28-2011).

Results

26Rothberg MB, et al. Antibiotic therapy and treatment failure in patients hospitalized for acute exacerbations of chronic obstructive pulmonary disease. JAMA. May 2010;303(20):2035-2042.

Treatment Failure Length of Stay & Cost

Non-Hospitalized Exacerbation Patients

• Study design: Systematic review

• Objective

• Study subjects

27Ram FSF, et al. Antibiotics for exacerbations of chronic obstructive pulmonary disease (Review). Cochrane Database Sys. Rev. (2): CD004403, 2006.

Results

28Ram FSF, et al. Antibiotics for exacerbations of chronic obstructive pulmonary disease (Review). Cochrane Database Sys. Rev. (2): CD004403, 2006.

Current Guidelines

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GOLD Guidelines

Antibiotics should be given to patients with:

• All 3 cardinal symptoms:– dyspnea– sputum volume– sputum purulence

• 2 of the cardinal symptoms if sputum purulence included

• Severe exacerbation requiring mechanical ventilation30Global Strategy for the Diagnosis, Management and Prevention of COPD, 2010. Available from: http://www.goldcopd.org.

Application of Research Data

• Continue to use antibiotics in severe exacerbations requiring mechanical ventilation

• Limit antibiotic use to those patients requiring hospitalization for their exacerbation

• Administer antibiotics early, if necessary, within first 2 days of hospital admission

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Future Directions: Serum C-Reactive Protein (CRP) Guidance

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Subgroup Analysis in Doxycycline Study

Daniels, et al. Antibiotics in addition to systemic corticosteroids for acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2010;181:150-157.

Future Directions:Procalcitonin Guidance

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• Randomized controlled trial

• Standard therapy group vs. procalcitonin group

• Equivalent clinical success rate (p = 0.853)

Stolz D, et al. Antibiotic treatment of exacerbations of COPD: a randomized, controlled trial comparing procalcitonin-guidance with standard therapy. Chest 2007;131:9-19.

Review of Topics

• COPD overview– Epidemiology, definition, and pathogenesis

• Current research

• Current guidelines

• Recommendations

• Future directions

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Questions?

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